ß-adrenergic signaling is a master regulator in the fight-or-flight response, potentiating rapid enhancements to cardiac function in stressful environments. However, misregulation of ß-adrenergic signaling also drives the development of cardiac failure. Here, we will be discussing recent work investigating compartmentation mechanisms regulating the ß-adrenergic signaling specificity and the relevance to cardiac physiology and disease.